The following compounds and the method of preparation thereof are disclosed in (1) Chemical Abstracts, vol. 55, column 23488 (1961), (2) Nippon Kagaku Zassi, vol. 83-3, pp. 343-347 (1962), [Chemical Abstracts, vol. 59, column 3862 (1963)], (3) Chemical Abstracts, vol. 64, column 586 (1966), (4) Chemical Abstracts, vol. 69, 18565.times. (1968), (5) U.S. Pat. No. 4,735,940, column 39, lines 50-51 and (6) Journal of Heterocyclic Chemistry, vol. 13, pp. 1347-1349 (1976). ##STR2##
On the other hand, compounds having antipsychotic activity are known by patent publications such as JP-A S60-84282, JP-A S59-227882, JP-A S58-90583, JP-A S63-132887, JP-A S63-183576, JP-A H1-199967 and JP-A H4-308584.
Antipsychotic drugs introduced in 1950's have been played a large role in treating schizophrenia.
In 1960's "dopamine hypothesis" concerned with schizophrenia has been suggested (Carlsson, A. et al, Acta. Pharmacol. Toxicol. 20, 140-144 (1963)) and the strong correlation between the affinity of antipsychotic drugs for D.sub.2 receptors in striatum and the average clinical dose have been reported (Seeman, P. et al, Nature, 261, 717-719 (1976), Creese, I. et al, Science, 192, 481-483 (1976)). After that, the concept of the development of antipsychotic drugs was the blockade of D.sub.2 receptors. However, typical antipsychotic drugs are effective for the treatment of the positive symptoms such as hallucination and delusions, but not effective for that of the negative symptoms such as apathy and social withdrawal (Zubin, J. et al, Comprehensive Psychiatry, 26, 217-240 (1985)). And the extrapyramidal side-effect (EPS: dystonia, akathidia, tardive dyskinesia) and the elevation in the level of serum prolactin in the acute and chronic treatment of typical antipsychotic drugs are the serious problems for patients.
From these points of view, the development of a typical antipsychotic drugs, produce fewer EPS and are more effective than typical antipsychotic drugs in treating schizophrenia, is desired.
The profile of atypical antipsychotic drug are as follows.
1) It is effective for both positive and negative symptoms. PA1 2) It produces fewer EPS. PA1 3) It has no side-effect of internal secretion. PA1 1. a condensed thiophene compound of the formula: ##STR3## or a pharmaceutical acceptable salt thereof. PA1 2. the compound of the above-mentioned item 1 or a pharmaceutically acceptable salt thereof, wherein T is a tertiary amino of --N(Rb)(Rc) [Rb and Rc are the same or different and each is alkyl, or Rb and Rc together with the adjacent nitrogen atom form a cyclic amino of the formula: ##STR5## wherein q is an integer of 1 to 4, Z is methylene, or N--R.sup.5 (R.sup.5 is aryl, diarylalkyl, heteroaryl or heteroarylalkyl), substituent V is hydrogen, hydroxyl, heteroaryl, heteroarylalkyl or bisarylmethylene and the number of V is 1 to 4. Cyclic amino of formula (1) may contain carbonyl group in the cycle and further may be condensed with aryl or heteroaryl. Ring Am of formula (2) contain amido bond in the cycle and further may contain oxygen atom, sulfur atom, carbonyl and/or N--R.sup.6 (R.sup.6 is hydrogen, alkyl or phenyl). PA1 3. preferable compound of the above-mentioned item 1 selected from the group consisting of: PA1 4. Preferable compound of the above-mentioned item 1 selected from the group consisting of: PA1 5. a condensed thiophene compound of the formula: ##STR6## wherein X is hydroxyl, or a reactive atom or group derived from hydroxyl (halogen, methanesulfonyloxy, p-toluenesulfonyloxy and so on), and other symbols are as defined in the above-mentioned item 1; PA1 6. a pharmaceutical composition comprising a compound of the above-mentioned item 1 and pharmaceutical additives; PA1 7. an antipsychotic drug containing a compound of the above-mentioned item 1 as an effective ingredient.
1. Merits by addition of 5-HT.sub.2 receptor antagonistic activity:
In clinical study, it has been reported that the selective 5-HT.sub.2 antagonist ritanserin ameliorates negative symptoms and reduces the incidence of EPS caused by typical antipsychotic drug therapy (Bersani, G. et al, Curr. Ther. Res., 10, 492-499 (1986)). And in preclinical study, it has also been reported that 5-HT.sub.2 antagonists reduced catalepsy induced by haloperidol (Hicks, P. B., Life Sci., 47, 1609-1615 (1990)). On the other hand, syndrome malin induced by neuroleptics is the unbalance of dopaminergic and serotonergic activity in the center of the regulation of temperature has been proposed (Yamawaki, N., Sinkeiseisinyakuri, 11, 17-24 (1989). Therefore, it is expected that additional 5-HT.sub.2 receptor antagonism reduces the syndrome malin.
Risperidone has extremely potent 5-HT.sub.2 and potent D.sub.2 receptor antagonistic properties (Janssen, P. A. J. et al, J. Pharmacol. Exp. Ther. 244, 685-693 (1988)), and has revealed a clinical profile that is distinct from that of existing neuroleptics. Risperidone proved to be an effective antipsychotic, with low EPS liability and with beneficial effects on the negative symptoms of schizophrenia (The 1st International Risperidone Investigator's Meeting (Conference Review), Paris (France), Mar. 9-10, 1992), but it has not a character of atypical antipsychotic drug yet because EPS is appeared in high dose of risperidone and it has side-effect of internal secretion yet.
2. Merits by addition of 5-HT.sub.1A agonist:
5-HT.sub.1A agonist has been reported to be possible to make up for the disadvantage of typical antipsychotic drugs, because 5-HT.sub.1A agonist buspirone improved the depression and EPS caused by haloperidol therapy in clinical study (McMillen, B. A. et al, J. Pharma. Pharmacol., 40, 885-887 (1988)). And, it is supported to the above mentioned possibility that 5-HT.sub.1A agonist 8-OH DPAT and buspirone reverse catalepsy induced by haloperidol in preclinical study (Goff, D. C. et al, J. Clin. Psychopharmacol. 11, 193-197 (1991)), Invernizzi, R. W. et al, Neuropharmacology, 27, 515-518 (1988)). And then, amplification of antipsychotic effect by additional 5-HT.sub.1A agonistic activity is expected, because administration of 8-OH DPAT with D.sub.2 antagonist inhibit conditioned avoidance response (CAR) more potent than that of D.sub.2 antagonist only (Wadenberg, M. L. et al, J. Neural. Transm. 83, 43-53 (1991)).
3. The functional relationships of 5-HT.sub.1A receptors and 5-HT.sub.2 receptors:
By the study of electrical physiology and biochemistry, it has been revealed that 5-HT.sub.1A and 5-HT.sub.2 receptors regulate the serotonergic activity through the K channel (second messenger system in cell) (Bobker, H. H. et al, Trends Neurosci., 13, 169-173 (1990)). Stimulation of 5-HT.sub.1A receptor makes a hyperpolarization, and stimulation of 5-HT.sub.2 receptor makes a depolarization. Therefore, both 5-HT.sub.1A agonist and 5-HT.sub.2 antagonist inhibit the serotonergic activity, and the inhibition of serotonergic activity is amplified if 5-HT.sub.1A agonistic and 5-HT.sub.2 antagonistic activities are occurred at the same time. This is supported by the preclinical pharmacological data that anxiolitic and antidepressant effects of 5-HT.sub.1A agonist are reinforced by addition of 5-HT.sub.2 antagonist (Millan, M. J. et al, J. Neural. Transm. 83, 43-53 (1991)).
As mentioned above, it has been reported that the disadvantages of typical antipsychotic drugs are improved by addition of 5-HT.sub.2 antagonistic and 5-HT.sub.1A agonistic activities to the typical antipsychotic drugs (D.sub.2 antagonists). Especially, negative symptoms must be distinguished from depression, but in either symptoms the desired pharmacological effect is activation, and it is suggested that the addition of 5-HT.sub.1A agonistic activity, that improves the depression, improves the negative symptoms like 5-HT.sub.2 antagonistic activity.
As mentioned above, the amplificational effect of serotonergic activity are expected by addition of both 5-HT.sub.1A agonist and 5-HT.sub.2 antagonist, therefore it is expected that the addition of both 5-HT.sub.1A agonist and 5-HT.sub.2 antagonist to D.sub.2 antagonist is more effective to the negative symptoms than the addition of either of them to it.